Study of the inflamassoma NLRP3 in the inflammatory response induced by the dimorphic fungus Paracoccidioides brasiliensis

Abstract

Fungal infections are currently amongst the most life thre between the most important diseases. In immunocompromised individuals paracoccidioidomycosis (PCM) caused by Paracoccidoides brasiliensis is the most important systemic mycosis in Brazil. Studies concerning the immune response in PCM infection are scarce specially involving the initial events of the disease. The inflammatory response is extremely important to control the disease; however, an exacerbated inflammation can cause tissue damage and imbalance of the immune response. The inflammatory response is initiated by the recognition of fungal cells through receptors expressed by cells of the innate immune system. Recently, a new family of receptors (NOD-like receptors or NLRs) was described and it is involved in the recognition of molecules expressed by pathogens and stress signals produced during infection or cellular damage. Some NLRs participate in the assembling of a multiproteic complex called inflammasoma that active caspase-1, which is responsible for the production of actives forms of two important cytokines: IL-1b and IL-18. Among NLRs, the NLRP3 was associated with the recognition of pathogenic fungi such as C. albicans and Aspergillus fumigatus in experimental models, working in association with TLR2 and dectin-1. However, there are still no data supporting a role for these receptors in the context of PCM infection; although some evidences can suggest the involvement of these receptors, mostly in the production of IL-1b and IL-18, abundant in the lesions and in peripheral blood of patients with the disease. This study aim to investigate a possible involvement of NLRP3 in the activation of the inflammatory response of macrophages and dendritic cells in response to P. brasiliensis and determine if this receptor is involved in the development of the adaptive response. Thus, this study could contribute to expand our knowledge about the function of the NLRs and a possible role in the initial response against pathogens, not only P. brasiliensis, but in other systemic fungal infections. (AU)